The long term objectives of this program are to elucidate the pathogenesis of liver cell injury and hepatocellular carcinoma in hepatitis B virus (HBV) infection. The unifying factor in all of these studies is our interest in the viral and host determinants, and the virus-host interac- tions, that are involved in the pathogenesis of this disease. Because HBV is not infectious in tissue culture and it does not infect immunologically well characterized laboratory animals, the pathogenic mechanisms respon- sible for liver cell injury and hepatocellular carcinoma in this infection are unknown. A transgenic mouse model of HBV expression has been created specifically to provide the opportunity and the reagents needed to pursue these questions directly and definitively. This model has already produced important new insights into the immunobiology and pathogenesis of liver cell injury and hepatocellular carcinoma especially with respect to the role of the viral envelope polypeptides. During the course of the next several years many of the ongoing studies will be continued, and the program will be expanded to the remaining HBV gene products. New lineages that replicate the viral genome and that express the remaining viral gene products under the control of a regulatab- le, liver specific promoter will be produced. The structural, functional and pathogenic effects of overexpression of each of the viral gene products will be examined. The influence of the acute phase response on hepatocel- lular HBV gene expression and viral replication will be analyzed. Com- plementation studies elucidating the role of nucleocapsid-envelope interac- tions in viral structure and pathogenesis will be performed. In immunolog- ical studies, the repertoire of cytotoxic T cell (CTL) responses to each of the viral antigens will be defined in order to determine which of the viral gene products are important with respect to the induction of hepatocellular injury. The conditions necessary to induce severe, chronic immunologically mediated liver cell injury will be established in order to determine whether such a disease will lead to the development of hepatocellular carcinoma. The ability of tumor specific CTL to prevent and reverse the development of hepatocellular carcinoma in this model will be assessed. Finally, the basis for immunological tolerance to the HBV-encoded antigens will be explored. We anticipate that these studies will lead to a better understanding of the pathogenesis of liver cell injury and hepatocellular carcinoma in this serious disease.